This invention relates to the novel processes for the preparation of 9,11-epoxy steroid compounds, especially those of the 20-spiroxane series and their analogs, novel intermediates useful in the preparation of steroid compounds, and processes for the preparation of such novel intermediates. Most particularly, the invention is directed to novel and advantageous methods for the preparation of methyl hydrogen 9,11xcex1-epoxy-17xcex1-hydroxy-3-oxopregn-4-ene-7xcex1,21-dicarboxylate, xcex3-lactone (also referred to as eplerenone or epoxymexrenone).
Methods for the preparation of 20-spiroxane series compounds are described in U.S. Pat. No. 4,559,332. The compounds produced in accordance with the process of the ""332 patent have an open oxygen containing ring E of the general formula: 
in which
xe2x80x94Axe2x80x94Axe2x80x94 represents the group xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94;
R1 represents an xcex1-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;
xe2x80x94Bxe2x80x94Bxe2x80x94 represents the group xe2x80x94CH2xe2x80x94CH2xe2x80x94 or an xcex1- or xcex2-oriented group; 
R6 and R7 being hydrogen;
X represents two hydrogen atoms or oxo;
Y1 and Y2 together represent the oxygen bridge xe2x80x94Oxe2x80x94, or
Y1 represents hydroxy, and
Y2 represents hydroxy, lower alkoxy or, if X represents H2, also lower alkanoyloxy;
and salts of such compounds in which X represents oxo and Y2 represents hydroxy, that is to say of corresponding 17xcex2-hydroxy-21-carboxylic acids.
U.S. Pat. No. 4,559,332 describes a number of methods for the preparation of epoxymexrenone and related compounds of Formula IA. The advent of new and expanded clinical uses for epoxymexrenone create a need for improved processes for the manufacture of this and other related steroids.
The primary object of the present invention is the provision of improved processes for the preparation of epoxymexrenone, other 20-spiroxanes and other steroids having common structural features. Among the particular objects of the invention are: to provide an improved process that produces products of Formula IA and other related compounds in high yield; the provision of such a process which involves a minimum of isolation steps; and the provision of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost.
Accordingly, the present invention is directed to a series of synthesis schemes for epoxymexrenone; intermediates useful in the manufacture of epoxymexrenone; and syntheses for such novel intermediates.
The novel synthesis schemes are described in detail in the Description of Preferred Embodiments. Among the novel intermediates of this invention are those described immediately below.
A compound of Formula IV corresponds to the structure: 
wherein:
xe2x80x94Axe2x80x94Axe2x80x94 represents the group xe2x80x94CHR4xe2x80x94CHR5xe2x80x94 or xe2x80x94CR4xe2x95x90CR5xe2x80x94;
R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano and aryloxy;
R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical;
R2 is an 11xcex1-leaving group the abstraction of which is effective for generating a double bond between the 9- and 11-carbon atoms;
xe2x80x94Bxe2x80x94Bxe2x80x94 represents the group xe2x80x94CHR6xe2x80x94CHR7xe2x80x94 or an alpha- or beta-oriented group: 
where
R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy; and
R8 and R9 are independently selected from the group consisting of hydrogen, hydroxy, halo, lower alkoxy, acyl, hydroxyalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano and aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.
A compound of Formula IVA corresponds to Formula IV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula IVB corresponds to Formula IV wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae IVC, IVD and IVE, respectively, correspond to any of Formula IV, IVA, or IVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, R3 is hydrogen, and R1 is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula IV may be prepared by reacting a lower alkylsulfonylating or acylating reagent, or a halide generating agent, with a corresponding compound within the scope of Formula V.
A compound of Formula V corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R1, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VA corresponds to Formula V wherein R8 and R9 with the ring carbon to which they are attached together form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VB corresponds to Formula V wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VC, VD and VE, respectively, correspond to any of Formula V, VA, or VB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, R3 is hydrogen, and R1 is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula V may be prepared by reacting an alkali metal alkoxide with a corresponding compound of Formula VI.
A compound of Formula VI corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIA corresponds to Formula VI wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIB corresponds to Formula VI wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIC, VID and VIE, respectively, correspond to any of Formula VI, VIA, or VIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds of Formula VI, VIA, VIB and VIC are prepared by hydrolyzing a compound corresponding to Formula VII, VIIA, VIIB or VIIC, respectively.
A compound of Formula VII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIIA corresponds to Formula VII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIIB corresponds to Formula VII wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIIC, VIID and VIIE, respectively, correspond to any of Formula VII, VIIA, or VIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. A compound within the scope of Formula VII may be prepared by cyanidation of a compound within the scope of Formula VIII.
A compound of Formula VIII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIIIA corresponds to Formula VIII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIIIB corresponds to Formula VIII wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIIIC, VIIID and VIIIE, respectively, correspond to any of Formula VIII, VIIIA, or VIIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula VIII are prepared by oxidizing a substrate comprising a compound of Formula XXX as described hereinbelow by fermentation effective for introducing an 11-hydroxy group into the substrate in xcex1-orientation.
A compound of Formula IX corresponds to the structure: 
where xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV, and R1 is as defined in Formula V.
A compound of Formula IXA corresponds to Formula IX wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula IXB corresponds to Formula IX wherein R8 and R9 together with the ring carbon to which they are attached form the structure of Formula XXXIII: 
Compounds of Formulae IXC, IXD and IXE, respectively, correspond to any of Formula IX, IXA, or IXB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula IX can be prepared by bioconversion of a corresponding compound within the scope of Formula X.
A compound of Formula XIV corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XIVA corresponds to Formula XIV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XIVB corresponds to Formula XIV wherein R8 and R9 together with the ring carbon to which they are attached form the structure of Formula XXXIII: 
Compounds of Formulae XIVC, XIVD and XIVE, respectively, correspond to any of Formula XIV, XIVA, or XIVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XIV can be prepared by hydrolysis of a corresponding compound within the scope of Formula XV.
A compound of Formula XV corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XVA corresponds to Formula XV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XVB corresponds to Formula XV wherein R8 and R9 together with the ring carbon to which they are attached form the structure of Formula XXXIII: 
Compounds of Formulae XVC, XVD and XVE, respectively, correspond to any of Formula XV, XVA, or XVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XV can be prepared by cyanidation of a corresponding compound within the scope of Formula XVI.
A compound of Formula XXI corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIA corresponds to Formula XXI wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIB corresponds to Formula XXI wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIC, XXID and XXIE, respectively, correspond to any of Formula XXI, XXIA, or XXIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXI may be prepared by hydrolyzing a corresponding compound within the scope of Formula XXII.
A compound of Formula XXII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIIA corresponds to Formula XXII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIIB corresponds to Formula XXII wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIIC, XXIID and XXIIE, respectively, correspond to any of Formula XXII, XXIIA, or XXIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXII may be prepared by cyanidation of a compound within the scope of Formula XXIII.
A compound of Formula XXIII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIIIA corresponds to Formula XXIII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIIIB corresponds to Formula XXIII wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIIIC, XXIIID and XXIIIE, respectively, correspond to any of Formula XXIII, XXIIIA, or XXIIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXIII can be prepared by oxidation of a compound of Formula XXIV, as described hereinbelow.
A compound of Formula XXVI corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXVIA corresponds to Formula XXVI wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXVI can be prepared by oxidation of a compound of Formula XXVII.
A compound of Formula XXV corresponding to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXVA corresponds to Formula XXV wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXV can be prepared by cyanidation of a compound of Formula XXVI.
A compound of Formula 104 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV, and R11 is C1 to C4 alkyl.
A compound of Formula 104A corresponds to Formula 104 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 104 may be prepared by thermal decomposition of a compound of Formula 103.
A compound of Formula 103 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104, and R12 is a C1 to C4 alkyl.
A compound of Formula 103A corresponds to Formula 103 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 103 may be prepared by reaction of a corresponding compound of Formula 102 with a dialkyl malonate in the presence of a base such as an alkali metal alkoxide.
A compound of Formula 102 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104.
A compound of Formula 102A corresponds to Formula 102 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 102 may be prepared by reaction of a corresponding compound of Formula 101 with a trialkyl sulfonium compound in the presence of a base.
A compound of Formula 101 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104.
A compound of Formula 101A corresponds to Formula 101 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 101 may be prepared by reaction of 11xcex1-hydroxyandrostene-3,17-dione or other compound of Formula XXXVI with a trialkyl orthoformate in the presence of an acid.
A compound of Formula XL corresponds to the Formula: 
wherein xe2x80x94Exe2x80x94Exe2x80x94 is selected from among: 
R21, R22 and R23 are independently selected from among hydrogen, alkyl, halo, nitro, and cyano; R24 is selected from among hydrogen and lower alkyl; R80 and R90 are independently selected from keto and the substituents that may constitute R8 and R9 (as defined hereinabove with reference to Formula IV); and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV.
A compound of Formula XLA corresponds to Formula XL wherein R21, R22 and R23 are independently selected from among hydrogen, halogen and lower alkyl.
A compound of Formula XLB corresponds to Formula XLA wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII. A compound of Formula XLC corresponds to Formula XLB wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLV. A compound of XLD corresponds to Formula XLB wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLVII.
A compound of Formula XLE corresponds to Formula XL wherein R80 and R90 together with the ring carbon atom to which they are attached comprise keto or: 
where X, Y1, Y2 and C(17) are as defined above, or 
Compounds of Formula XLIE correspond to Formula XL in which R80 and R90 together form keto.
Compounds of Formulae XLF, XLG, XLH, XLJ, XLM, and XLN correspond to Formula XL, XLA, XLB, XLC, XLD and XLE, respectively, in which xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined above.
A compound of Formula XLI corresponds to the Formula: 
wherein xe2x80x94Exe2x80x94Exe2x80x94 is selected from among: 
R18 is C1 to C4 alkyl or the R18O-groups together form an O,O-oxyalkylene bridge; R21, R22 and R23 are independently selected from among hydrogen, alkyl, halo, nitro, and cyano; R24 is selected from among hydrogen and lower alkyl; R80 and R90 are independently selected from keto and the substituents that may constitute R8 and R9; and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV.
A compound of Formula XLIA corresponds to Formula XLI wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula XLIB corresponds to Formula XLIA wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
A compound of Formula XLIC corresponds to Formula XLI wherein R80 and R90 together with the ring carbon atom to which they are attached comprise keto or: 
where X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae XLID correspond to Formula XLI in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formula XLIE correspond to Formula XL in which R80 and R90 together form keto.
Compounds of Formulae XLIF, XLIG, XLIH, XLIJ, XLIM, and XLIN correspond to Formula XLI, XLIA, XLIB, XLIC, XLID and XLIE, respectively, in which xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined above. Compounds within the scope of Formula XLI are prepared by hydrolysis of corresponding compounds of Formula XL as defined hereinbelow.
A compound of Formula XLII corresponds to the Formula: 
wherein xe2x80x94Exe2x80x94Exe2x80x94 is selected from among: 
R21, R22 and R23 are independently selected from among hydrogen, alkyl, halo, nitro, and cyano; R24 is selected from among hydrogen and lower alkyl; R80 and R90 are independently selected from keto and the substituents that may constitute R8 and R9; and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV.
A compound of Formula XLIIA corresponds to Formula XLII wherein R21, R22 and R23 are independently selected from among hydrogen, halogen and lower alkyl.
A compound of Formula XLIIB corresponds to Formula XLIIA wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
A compound of Formula XLIIC corresponds to Formula XLII wherein R80 and R90 together with the ring carbon to which they are attached comprise keto or: 
where X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae XLIID correspond to Formula XLII in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formula XLIIE correspond to Formula XLII in which R80 and R90 together form keto. Compounds of Formulae XLIIF, XLIIG, XLIIH, XLIIJ, XLIIM and XLIIN correspond to Formulae XLII, XLIIA, XLIIB, XLIIC, XLIID and XLIIE, respectively, in which xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 are xe2x80x94CH2xe2x80x94CH2 and R3 is hydrogen. Compounds within the scope of Formula XLII are prepared by deprotecting a corresponding compound of Formula XLI.
A compound of the Formula XLIX corresponds to the structure: 
wherein xe2x80x94Exe2x80x94Exe2x80x94 is as defined in Formula XL, and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R1, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XLIXA corresponds to Formula XLIX wherein R8 and R9 with the ring carbon to which they are attached together form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XLIXB corresponds to Formula XLIX wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XLIXC, XLIXD, XLIXE, respectively, correspond to any of Formula XLIX, XLIXA or XLIXB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, R3 is hydrogen and R1 is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula XLIX may be prepared by reacting an alcoholic or aqueous solvent with a corresponding compound Formula VI in the presence of a suitable base.
A compound of Formula A203 corresponds to the structure: 
wherein xe2x80x94Exe2x80x94Exe2x80x94 is selected from among: 
R18 is selected from among C1 to C4 alkyl; R21, R22 and R23 are independently selected from among hydrogen, alkyl, halo, nitro, and cyano; R24 is selected from among hydrogen and lower alkyl; and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV.
A compound of Formula A203A corresponds to Formula A203 wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A203B corresponds to Formula A203A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
Compounds of Formulae A203C, A203D, and A203E respectively correspond to Formula A203, A203A and A203B wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A203 are prepared by reducing a compound of Formula A202 as defined hereinbelow.
A compound of Formula A204 corresponds to the structure: 
wherein R19 is C1 to C4 alkyl, and xe2x80x94Exe2x80x94Exe2x80x94, xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula 203.
A compound of Formula A204A corresponds to Formula A204 wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A204B corresponds to Formula A204A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
Compounds of Formulae A204C, A204D, and A204E respectively correspond to Formulae A204, A204A, and A204B wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A204 are prepared by hydrolysis of corresponding compounds of Formula A203.
A compound of Formula A205 corresponds to the structure: 
wherein R20 is C1 to C4 alkyl, and xe2x80x94Exe2x80x94Exe2x80x94, R19, xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula 204.
A compound of Formula A205A corresponds to Formula A205 wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A205B corresponds to Formula A205A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
Compounds of Formulae A205C, A205D and A205E respectively correspond to Formula A205, A205A and A205B wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A205 may be prepared by reacting a corresponding compound of Formula A204 with an alkanol and acid.
A compound of Formula A206 corresponds to the structure: 
wherein R19, R20, xe2x80x94Exe2x80x94Exe2x80x94, xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula 205.
A compound of Formula A206A corresponds to Formula A206 wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A206B corresponds to Formula A206A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
Compounds of Formulae A206C, A206D and A206E respectively correspond to Formula A206, A206A, and A206B wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A206 may be prepared by reacting a corresponding compound within the scope of Formula A205 with a trialkyl sulfonium halide.
A compound of Formula A207 corresponds to the structure: 
wherein R25 is C1 to C4 alkyl, and xe2x80x94Exe2x80x94Exe2x80x94, R19, R20, xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula A205.
A compound of Formula A207A corresponds to Formula A207 wherein R21, R22 and R23 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A207B corresponds to Formula A207A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
Compounds of Formulae A207C, A207D and A207E respectively correspond to Formula A207, A207A and A207B wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds of Formula A207 can be prepared by reaction of compounds of Formula A206 with a dialkyl malonate.
A compound of Formula A208 corresponds to the structure: 
wherein xe2x80x94Exe2x80x94Exe2x80x94, R80 and R90 are as defined in Formula XLII; xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula 104; and R19, R20, xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, and R3 are as defined in Formula 205.
A compound of Formula A208A corresponds to Formula A208 wherein R21 and R22 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A208B corresponds to Formula A208A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
A compound of Formula A208C corresponds to Formula A208 wherein R80 and R90 together with the ring carbon to which they are attached comprise keto or: 
where X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae 208D correspond to Formula 208C in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formulae A208E, A208F, A208G, A208H and A208J respectively correspond to Formula A208, A208A, A208B, A208C and A208D wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A208 can be prepared by thermal decomposition of corresponding compounds of Formula A207.
A compound of Formula A209 corresponds to the structure: 
wherein R80 and R90 are as defined in Formula XLI, and xe2x80x94Exe2x80x94Exe2x80x94 and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, and R3 are as defined in Formula 205.
A compound of Formula A209A corresponds to Formula A209 wherein R21 and R22 are independently selected from among hydrogen, halogen, and lower alkyl.
A compound of Formula A209B corresponds to Formula A209A wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIII, XLIV, XLV or XLVII.
A compound of Formula A209C corresponds to Formula A209B wherein xe2x80x94Exe2x80x94Exe2x80x94 corresponds to Formula XLIV.
A compound of Formula A209D corresponds to Formula A208 wherein R80 and R90 together with the ring carbon to which they are attached comprise keto or: 
where X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae 209E correspond to Formula A209D in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formulae A209F, A209G, A209H, A209J, A209L, and A209M respectively correspond to Formula A209, A209A, A209B, A209C, A209D and A209E wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A209 may be prepared by hydrolysis of a corresponding compound of Formula A208.
A compound of Formula A210 corresponds to the structure: 
wherein R80 and R90 are as defined in Formula XLI, and the substituents xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as defined in Formula IV.
A compound of Formula A210A corresponds to Formula A210 wherein R80 and R90 together with the ring carbon to which they are attached comprise keto or: 
wherein X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae A210B correspond to Formula A210A in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formula A210C correspond to Formula A210A in which R80 and R90 together form keto.
Compounds of Formulae A210D, A210E, A210F and A210G respectively correspond to Formula A210, A210A, A210B and A210C wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94 and and R3 is hydrogen. Compounds within the scope of Formula 210 can be prepared by epoxidation of a compound of Formula 209 in which xe2x80x94Exe2x80x94Exe2x80x94 is 
A compound of Formula A211 corresponds to the Formula 
where xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94 and R3 are as described above.
A compound of Formula A211A corresponds to Formula A211 wherein R80 and R90 together comprise keto or: 
wherein X, Y1, Y2 and C(17) are as defined above.
Compounds of Formulae A211B correspond to Formula A211A in which the substituent XXXIV corresponds to the structure XXXIII 
Compounds of Formula A211C correspond to Formula A210A in which R80 and R90 together form keto.
Compounds of Formulae A211D, A211E, A211F, and A211G, respectively correspond to Formula A211, A211A, A211B and A211C wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula A211 can be prepared by oxidation of a corresponding compound of Formula A210, or in the course of epoxidation of the corresponding compound of Formula A209 where xe2x80x94Exe2x80x94Exe2x80x94 is 
Compounds of Formula A211 may be converted to compounds of Formula I in the manner described hereinbelow.
A compound of Formula L corresponds to the structure: 
wherein R11 is C1 to C4 alkyl, and xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R1, R2, R3, R8 and R9 are as defined above.
Compounds of Formula LA correspond to Formula L wherein R8 and R9 together with the carbon atom to which they are attached comprises 
wherein X, Y1 and Y2 are as defined above.
Compounds of Formula LB correspond to Formula L wherein R8 and R9 correspond to Formula XXXIII 
Compounds of Formulae LC, LD, LE correspond to Formulae L, LA and LB, respectively, where xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 are each xe2x80x94CH2xe2x80x94CH2xe2x80x94 and R3 is hydrogen.
Based on the disclosure of specific reaction schemes as set out hereinbelow, it will be apparent which of these compounds have the greatest utility relative to a particular reaction scheme. The compounds of this invention are useful as intermediates for epoxymexrenone and other steroids.
Other objects and features will be in part apparent and in part pointed out hereinafter.